This application focuses on the central goals of the RFA for Centers for Medical Countermeasures Against Radiation by: (a) identifying countermeasure strategy that mitigates delayed radiation injury, (2) characterizing injury and countermeasures in the susceptible pediatric population, and (3) applying countermeasures that treat radiation and infection combined injury. Multi-organ radiation-induced injury is a major threat during targeted terror attack, and adaptive and innate immunity are increasingly found to play a key role in this process. Innate immune receptors collectively referred to as Pathogen Recognition Receptors (PRR) have undergone an explosive discovery phase. Prominent PRR families include the membrane bound Toll-like receptors (TLR) which interact with extracellular ligands and NOD- like receptors which respond to intracellular agonists. These have been extensively studied in infection and inflammatory diseases, but their impact on radiation-induced damage (RID) is just emerging. Post-exposure, radiation not only causes acute injury but also delayed injury such as fibrosis and defective cellular and immune development. We and others have explored the roles of TLRs and NLRs during RID and unexpectedly found that TLRs and NLRs are protective of delayed radiation-induced damage. Common cytokines that are activated by PRR families are IL-1?? and IL-18. Indeed, deletion of IL-1? and/or IL-18 resulted in exacerbated clinical severity in the immune and susceptible organs of radiated mice. In this proposal, we will investigate how cytokines such as IL-1?? protects against delayed radiation-induced damage in solid organs. We will also address the same issue in immune cells. Finally, we will examine if the microbiome is altered in a gene-dependent way in response to radiation exposure.